Effectiveness of sirolimus for pediatric autoimmune cytopenias and factors associated with clinical response

Abstract Introduction Pediatric autoimmune cytopenias (pAICs) encompass a variety of disorders leading to destruction of ≥1 major hematopoietic cell line. AICs may be isolated or secondary to a diagnosis such as autoimmune lymphoproliferative syndrome (ALPS), systemic lupus erythematosus (SLE), or immune dysregulation/an immunodeficiency. First-line treatment typically includes the use of corticosteroids and/or IVIG, but these treatments present notable challenges of side effects and associated costs (such as the need for admission) and often lack sustained efficacy. Second-line agents are necessary when first-line treatments are poorly tolerated or ineffective, including options such as rituximab, mycophenolate mofetil, and thrombopoietin receptor agonists. These agents, however, also present challenges with ease of administration or associated side effects. Sirolimus is an mTOR inhibitor readily available in oral formulation and is generally well tolerated, with low rates of serious infection with long-term use. Evidence supporting the effectiveness of sirolimus in treating pAICs is limited, warranting the need for further studies. We seek to advance the understanding of when sirolimus should be trialed over other second-line agents and to identify factors that affect the likelihood of response. Methods We reviewed the charts of all pediatric patients at The Hospital for Sick Children in Toronto, Canada who started sirolimus for an AIC from Feb 2018 to Nov 2024. Patients were categorized into complete response (CR), partial response (PR), or no response (NR), based on the definitions below. Patients' diagnoses, bloodwork, demographics, side effects, and response to previous therapies were recorded. DefinitionsCR: Normalization of Hemoglobin (Hb) for age or platelets ≥100,000/mm3 for ≥2 consecutive monthsPR: Hb increase of ≥2 g/dL or platelets ≥50,000/mm3 for ≥2 consecutive monthsNR: Patients who could not be classified as having CR or PR Results Forty patients were included in our study; 15 (37.5%) had AICs secondary to diagnoses of ALPS/ALPS-like (n=3; 7%), SLE (n=4; 10%), immunodeficiency (n=6; 15%), Kabuki syndrome (n=1; 2.5%), and autoimmune myelofibrosis (AIM) (n=1; 2.5%). In patients with isolated AICs, 13 (32.5%) had immune thrombocytopenia (ITP) and 9 (22.5%) had Evans syndrome (1 with ITP and autoimmune hemolytic anemia, 8 with ITP and autoimmune neutropenia). The main indication for sirolimus was thrombocytopenia in 90% of patients vs anemia in 10%. The most common patient-reported side effects were oral ulcers (39%), acne (14.6%), rash (12.2%), and fatigue (9.8%). Five patients discontinued sirolimus due to side effects including jaw pain, exacerbation of a pre-existing rash, oral ulcers, headaches, and abdominal pain (n=1 for each). In 3 of these patients, CR had been achieved before discontinuation. For patients with NR, sirolimus was discontinued after a median of 2 months. CR/PR was achieved in 100% of those with Evans syndrome and 93.3% of those with a secondary cause of AIC, compared to only 46.2% in those with isolated ITP (p = 0.0013). The patient with Kabuki syndrome was the only non-responder with a secondary AIC. Therefore, 100% of patients with ALPS/ALPS-like, immunodeficiency, AIM, and SLE achieved a CR/PR in our study. The median time to CR/PR for all patients was 1 month, but labs could show improvement as early as 4 days after initiating sirolimus. Patients with isolated ITP (6 with CR, 7 with NR) were further analyzed to determine factors that may be associated with sirolimus response. Responders tended to be older (≥8 years) at AIC diagnosis (median 11 years CR vs 5.5 years NR) (p=0.836), had positive antinuclear antibody (ANA; 5/6 CR vs 2/7 NR) or direct-antiglobulin test (DAT; 3/6 CR vs 0/7 NR) (p=0.026), and were deemed refractory or minimally-responsive to first-line corticosteroids (4/6 CR vs 2/7 NR) and/or IVIG (4/6 CR vs 2/7 NR) (p=0.057). When all 3 factors were combined in a multivariable analysis, p=0.037. Conclusion Our work represents the largest ever study evaluating sirolimus to treat pAICs. Sirolimus is an effective and tolerable second-line agent in pediatric patients with Evans Syndrome or secondary AICs and should be strongly considered in such patients. In patients with isolated ITP, factors such as older age at diagnosis, positive ANA/DAT, and minimal/lack of response to first-line therapy are clinically relevant when deciding to trial sirolimus.